Engineering alpha fetoprotein and glypican-3 to develop hepatoma (HCC) vaccines

改造甲胎蛋白和磷脂酰肌醇蛋白聚糖 3 以开发肝癌 (HCC) 疫苗

• 批准号: 9231438
• 负责人: YUKAI HE
• 金额: $ 32.06万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231438
• 关键词: Adjuvant; Adjuvant Therapy; Adverse effects; Aftercare; Animal Model; Antigens; Autoimmune Hepatitis; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Etiology; Cancer Vaccines; Carcinogens; Cells; Cessation of life; Computational algorithm; Data; Dendritic Cells; Development; Diabetes Mellitus; Diethylnitrosamine; Engineering; Epitopes; Excision; Fright; GPC3 gene; Generations; Goals; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis C; Hepatitis C Prevalence; Hepatocyte; Human; Immune; Immune Targeting; Immune Tolerance; Immune system; Immunization; Immunologic Surveillance; Incidence; Individual; Infection; Lead; Legal patent; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Mono-S; Mus; Obesity; Operative Surgical Procedures; Outcome; Patient risk; Patients; Prevention; Primary carcinoma of the liver cells; Proteins; Recombinants; Recurrence; Relapse; Risk Factors; Survival Rate; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic Studies; Tissues; Transgenic Organisms; Transplantation; Tumor Antigens; United States; Vaccines; Virus-like particle; Work; alpha-Fetoproteins; antitumor effect; design; exhaustion; fighting; high risk; high risk population; immune activation; immunogenic; immunogenicity; innovation; killings; melanoma; memory CD4 T lymphocyte; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; pre-clinical; prevent; public health relevance; response; success; tumor; vaccine efficacy; vaccine evaluation; vaccinia virus vector

DESCRIPTION (provided by applicant): Liver cancer is the 5th most common cancer (748,000 cases a year) and the 3rd most common cause of cancer death (695,000 deaths a year) in the world. In the United States, while the incidence of many major cancers is declining, the incidence of hepatocellular carcinoma (HCC), the most common type of liver cancer, has almost tripled over the past two decades to ~20,000 per year. Despite the success of HBV vaccines to prevent new HBV infection, the large pool of existing HBV (350 million) and HCV (170 million) patients and the recent recognition that obesity/diabetes become a major risk factor of HCC in US suggest that HCC incidence will continue increasing over next few decades. Unfortunately, treatment options for HCC are limited, contributing to the dismal 17% 3-year survival rate. Liver resection and transplantation are curative for small tumors. But, the lac of adjuvant treatments after surgery is a critical barrier to the success of liver resection, which results in ~70% 5-year recurrence rate. Thus, there is an urgent need to develop novel approaches for HCC. Our long-term goal is to develop HCC vaccines to activate patient's immune system to conduct immune surveillance and thereby prevent HCC relapse or de novo development in high risk population. Approximately 84% of HCC (but not normal hepatocytes) express alpha fetoprotein (AFP), glypican 3 (GPC3), or both, making them excellent immune targets. However, they are self/tumor antigens and weakly immunogenic, and thus cannot effectively activate immune cells to generate significant antitumor effect. In this application, we propose to use murine autochthonous models to test the hypotheses that innovative approach of antigen engineering will increase the immunogenicity of HCC-associated self/tumor antigens of AFP and GPC3 to create effective HCC vaccines and that novel immunization strategy with the engineered HCC vaccines will induce potent and highly responsive memory T cells that conduct immune surveillance to prevent autochthonous HCC. The objectives are 1) to create immunogenic HCC vaccines, 2) to establish effective immunization strategy, and 3) to prevent autochthonous HCC. The outcomes will be the effective activation of immune system to prevent autochthonous HCC and generation of critical preclinical data that will help development of human HCC vaccine, which eventually lead to new therapy to fill the gap of HCC management after surgery. This will greatly benefit HCC patients who have undergone liver resection by preventing relapse and also offer an attractive option to prevent HCC de novo development in high risk populations who are living in the fear of developing HCC. This will bring about a radical change of HCC management, shifting the focus of cancer vaccine research from therapy to prevention, which is what a vaccine does best.

描述（由申请人提供）：肝癌是世界上第五大常见癌症（每年 748,000 例），也是第三大常见癌症死亡原因（每年 695,000 例死亡）。在美国，虽然许多主要癌症的发病率正在下降，但最常见的肝癌类型肝细胞癌 (HCC) 的发病率在过去二十年中几乎增加了两倍，达到每年约 20,000 例。尽管乙肝疫苗成功预防了新的乙肝病毒感染，但现有的大量乙肝病毒（3.5亿）和丙肝病毒（1.7亿）患者以及最近认识到肥胖/糖尿病成为美国肝癌的主要危险因素，表明肝癌发病率在未来几十年将继续增加。不幸的是，HCC 的治疗选择有限，导致 3 年生存率仅为 17%。肝切除和移植可治愈小肿瘤。但是，术后缺乏辅助治疗是肝切除成功的关键障碍。 结果5年复发率约为70%。因此，迫切需要开发治疗 HCC 的新方法。我们的长期目标是开发HCC疫苗来激活患者的免疫系统进行免疫监视，从而防止高危人群中HCC复发或从头发展。大约 84% 的 HCC（但不包括正常肝细胞）表达甲胎蛋白 (AFP)、磷脂酰肌醇蛋白聚糖 3 (GPC3) 或两者，使它们成为极好的免疫靶标。但它们是自身/肿瘤抗原，免疫原性较弱，无法有效激活免疫细胞产生显着的抗肿瘤作用。在这个应用程序中，我们 提议使用小鼠本地模型来测试以下假设：抗原工程的创新方法将增加 AFP 和 GPC3 的 HCC 相关自身/肿瘤抗原的免疫原性，以创建有效的 HCC 疫苗，并且工程化 HCC 疫苗的新免疫策略将诱导有效且高度反应的记忆 T 细胞，这些细胞进行免疫监视以预防本地 HCC。目标是 1) 制造免疫原性 HCC 疫苗，2) 建立有效的免疫策略，3) 预防原发性 HCC。结果将是有效激活免疫系统以预防原发性肝癌，并产生关键的临床前数据，这将有助于人类肝癌疫苗的开发，最终导致新的疗法填补术后肝癌管理的空白。这将极大地造福于接受肝切除术的 HCC 患者，防止复发，同时也为生活在担心罹患 HCC 的高危人群中预防 HCC 从头发展提供了一个有吸引力的选择。这将带来一场激进的 肝癌治疗的改变，将癌症疫苗研究的重点从治疗转向预防，这是疫苗最擅长的。